WO1999065058A2 - Parallel fluid electrospray mass spectrometer - Google Patents
Parallel fluid electrospray mass spectrometer Download PDFInfo
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- WO1999065058A2 WO1999065058A2 PCT/US1999/012905 US9912905W WO9965058A2 WO 1999065058 A2 WO1999065058 A2 WO 1999065058A2 US 9912905 W US9912905 W US 9912905W WO 9965058 A2 WO9965058 A2 WO 9965058A2
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- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
- H01J49/00—Particle spectrometers or separator tubes
- H01J49/02—Details
- H01J49/10—Ion sources; Ion guns
- H01J49/16—Ion sources; Ion guns using surface ionisation, e.g. field-, thermionic- or photo-emission
- H01J49/165—Electrospray ionisation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N2030/628—Multiplexing, i.e. several columns sharing a single detector
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/38—Flow patterns
- G01N30/46—Flow patterns using more than one column
- G01N30/466—Flow patterns using more than one column with separation columns in parallel
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
- G01N30/7233—Mass spectrometers interfaced to liquid or supercritical fluid chromatograph
- G01N30/724—Nebulising, aerosol formation or ionisation
- G01N30/7266—Nebulising, aerosol formation or ionisation by electric field, e.g. electrospray
Definitions
- the present invention relates to mass spectrometry, high performance liquid chromatography (HPLC) , and combinatorial chemistry.
- liquid chromatography-mass spectrometry systems can be used to purify fluid samples by first separating a fluid sample into its component compounds and then collecting only the desired component compounds found therein. Unfortunately, these systems suffer from several disadvantages .
- liquid chromatography-mass spectrometry systems have required that each fluid sample be analyzed in sequence. Parallel analysis of different fluid samples is not possible, for reasons which will be explained. Accordingly, the efficiency of combinatorial library analysis and purification is limited by the maximum speed at which the high performance liquid chromatograph-mass spectrometer (HPLC/MS) system can sequentially analyze each one of the various fluid samples so produced. Parallel analysis of different fluid samples is not possible with existing HPLC/MS systems because the mass spectrometer will simply generate a mass spectrum reading corresponding to all of the fluid being electrosprayed or otherwise received therein at any particular moment in time. As such, the mass spectrometer cannot distinguish between parallel electrosprays of different fluid samples simultaneously received therein.
- HPLC/MS high performance liquid chromatograph-mass spectrometer
- the mass spectrometer would simply analyze all of the various compounds found in all of the various simultaneously- received electrosprays. As such, it is not possible for the mass spectrometer to determine from which of a plurality of simultaneously-received electrosprays a particular sensed fluid compound was present .
- time is required to separate each fluid sample into its component compounds. The time required to separate each of the fluid samples must then be added together when sequentially performing liquid chromatography on a number of different fluid samples. Accordingly, a rather time-consuming process is required in which each fluid sample must be sequentially subjected to HPLC/MS .
- the present invention provides methods and systems for analyzing the composition of a plurality of fluid samples and more particularly for analyzing the mass spectrum of a plurality of fluid samples separated into component compounds by liquid chromatography and electrosprayed into a mass spectrometer.
- An important advantage of the present invention is that it allows simultaneous mass spectral analysis of each of the plurality of fluid samples using only a single mass spectrometer. Accordingly, the present invention requires substantially less time to analyze the composition of a plurality of fluid samples as compared to existing systems in which samples are analyzed sequentially by HPLC/MS.
- the present invention is able to distinguish between each of a plurality of fluid samples simultaneously electrosprayed from parallel liquid chromatography columns towards a mass spectrometer such that the mass spectra associated with each fluid sample can be reliably determined, as follows.
- a plurality of fluid samples is simultaneously separated by parallel liquid chromatography columns and are then simultaneously electrosprayed towards an entrance orifice of a mass spectrometer.
- a blocking device having an aperture passing therethrough is positioned so as to block all but one of the fluid samples from passing into the entrance orifice of the mass spectrometer at any moment in time.
- the blocking device and an array of electrospray needles connected to the columns are moved relative to one another so as to permit each effluent of the plurality of chromatographically-separated fluid samples to sequentially pass through the aperture in the blocking device and into the entrance orifice of the mass spectrometer one at a time.
- a rotating blocking device is moved relative to a plurality of stationary, equally spaced (i.e., arrayed) electrospray needles.
- the mass spectrometer thus analyzes each one of the chromatographically-separated fluid sample electrosprays received therein in turn.
- the mass spectrum of each electrosprayed fluid sample can be separately determined and distinguished from one another, regardless of the fact that each of the plurality of fluid samples are electrosprayed simultaneously out the exit ends of parallel electrospray needles.
- the blocking device is moved relative to the electrospray needles in a repetitive or cyclical manner such that each one of the fluid samples enters the mass spectrometer in turn again and again during the course of an LC/MS analysis.
- positioning and moving the blocking device comprises positioning a rotating disc between the electrospray needles and the mass spectrometer.
- the disc has a aperture passing therethrough which is dimensioned so as to permit only one of the plurality of fluid sample electrosprays to pass therethrough and enter the mass spectrometer.
- the fluid samples are simultaneously and continuously electrosprayed from parallel electrospray needles.
- the disc is then rotated such that each of the fluid sample electrosprays pass through the aperture and enter the mass spectrometer in turn.
- each of the fluid sample electrosprays will be analyzed again and again in a repeating pattern at a number of moments in time.
- each fluid sample is separated into its component compounds as it passes along through a chromatographic column, (since different compounds in each fluid sample take different amounts of time to pass therethrough) . Therefore, different component compounds in each fluid sample will be electrosprayed out of the end of each electrospray needle and be analyzed by the mass spectrometer at different moments in time. Accordingly, a varying mass spectrum reading will be generated for each of the plurality of fluid sample electrosprays over time.
- the fluid samples are simultaneously electrosprayed from an array of electrospray needles in trajectories which are parallel to one another.
- the fluid sample electrosprays are each targeted at locations on the rotating disc which are generally equidistant from the center of the disc and which each align with the center of the aperture of the disc as the disc is rotated. Accordingly, rotation of the disc moves the aperture relative to the array of parallel electrospray needles such that each one of the fluid samples sequentially passes through the aperture in the disc and is analyzed by the mass spectrometer in turn.
- the blocking device positioned between the electrospray needle array and the mass spectrometer comprises a plurality of high speed valves or shutters, (with each valve or shutter being dedicated to a particular electrospray needle) , which open and close one after another in sequence to permit each of the fluid samples to be electrosprayed into the mass spectrometer and analyzed in turn.
- the plurality of fluid samples are electrosprayed into the mass spectrometer one after another from respective electrospray needles in an array of electrospray needles, each connected to individual columns .
- the mass spectrometer preferably generates a continuous mass spectrum reading over a period of time.
- a mass spectrum reading for any particular fluid sample can be determined by sampling the continuous mass spectrum reading at the moments in time which correspond to when that particular fluid sample is being analyzed in the mass spectrometer. The exact moments in time when each fluid sample enters the mass spectrometer and is analyzed is determined by knowing the position of the aperture with respect to the fluid sample electrosprays over time. The mass spectrum reading of samples for any particular fluid sample will be expected to vary over time since each of the sample's component compounds will be eluted from the end of the column at different times.
- the preferred method also comprises a method of purifying each of the plurality of electrosprayed fluid samples.
- This method of purifying is ideally suited for use with a quadrupole mass spectrometer which detects the presence of positively or negatively charged gas phase ions corresponding to a particular molecular mass in a fluid sample corresponding to the voltage level applied across the quadrupole rods.
- the mass spectrometer can be adjustably set to detect the presence of various molecular masses in the ionized sample.
- each of the plurality of fluid sample electrosprays are directed into the mass spectrometer using any aspect of the above described method.
- the voltage across the mass spectrometer's quadrupole rods is incrementally stepped to a voltage level which corresponds to the molecular mass of a desired reaction product expected to be found in that particular fluid sample.
- Each fluid sample is then analyzed in turn at a voltage level corresponding to the desired reaction product expected to be found in the fluid sample.
- the rotation of the blocking disc is preferably synchronized with the stepping of the voltage level across the quadrupole rods such that the quadrupole rod senses the presence and concentration of the particular desired reaction product expected to be found in each fluid sample, as follows.
- a first fluid sample spray is analyzed at a first quadrupole rod voltage corresponding to the molecular mass of a desired reaction product expected to be found in this first fluid sample spray.
- the disc is then rotated such that a second fluid sample spray passes therethrough.
- the voltage is stepped to a second voltage level such that the second sample is analyzed by the quadrupole mass spectrometer at the second voltage corresponding to the molecular mass of a desired reaction product expected to be found in the second fluid sample spray.
- This process is repeated such that each fluid sample is analyzed in sequence with the concentration of the desired molecular mass corresponding to each fluid sample being determined.
- This method offers time efficiency advantages when analyzing fluid samples electrosprayed in parallel as only the desired reaction products in the various samples are monitored. Accordingly, a complete mass spectral analysis need not be performed on each fluid sample, and hence each electrosprayed fluid sample can be sampled more frequently, permitting increased numbers of parallel columns to be simultaneously analyzed in this aspect of the present invention.
- the fluid samples can be purified with fraction collection, as follows.
- fraction collection is performed such that when a desired molecular mass, (corresponding to a desired reaction compound) , is detected by the mass spectrometer to be in a sufficiently high concentration in a fluid sample spray, the flow of that fluid sample is diverted into a fraction collector. Only a small portion, (typically less than 1%) , of a fluid sample passing out of a column needs to be electrosprayed into the mass spectrometer for analysis.
- the present method comprises selective fraction collection at those moments in time when a desired reaction product appears in a sufficiently high concentration in a fluid sample. Accordingly, separate and simultaneous fraction collection of different desired reaction compounds found in the various fluid samples is achieved with each fluid sample being selectively collected at moments in time when the desired compound is being eluted from the end of the column. Accordingly, purification of each fluid sample is thus achieved by collecting the fluid sample only when the desired compound in the fluid sample is of a desirably high concentration .
- the preferred method also comprises a method of analyzing each of the individual fluid sample electrosprays so as to determine their composition.
- each of the plurality of fluid sample electrosprays are directed into the mass spectrometer as described herein.
- the present method of analyzing each fluid sample is ideally suited for use with various mass spectrometers, including quadrupole mass spectrometers and time-of-flight mass spectrometers and has the advantage that a complete fluid compositional analysis will be performed on each fluid sample, as follows.
- "analysis” may include quality control assessment (i.e., purity assessment) of compounds, screening compounds for biological activity against target enzyme or receptor, kinetic analysis, purification, high throughput pharmacokinetic profiling, and high throughput quantitation .
- the voltage across the quadrupole rods is preferably swept across a range of voltages for each fluid sample as each fluid sample is analyzed in turn.
- Each fluid sample is analyzed in turn such that a first sample is analyzed while the voltage swept across the entire voltage range, then a second sample is analyzed while the voltage again swept across the entire voltage range, etc.
- a complete mass spectral analysis determining the composition of each fluid sample is determined by detecting the presence of various molecular masses corresponding to different quadrupole rod voltage levels as the voltage level across the quadrupole rods is swept across the voltage range.
- the composition of each of the various fluid samples can also be analyzed in turn.
- An advantage of using a time-of-flight mass spectrometer is that time is not required to sweep a voltage across a range for each of the fluid sample electrosprays being analyzed by the mass spectrometer in turn, and therefore, the time required to perform a mass spectrum analysis is reduced significantly.
- the present invention also provides an apparatus for analyzing a plurality of fluid samples comprising a mass spectrometer, an electrospray needle array, and a blocking device dimensioned to selectively block all but one of the plurality of fluid samples from entering the mass spectrometer.
- the blocking device and the electrospray needle array are moveable with respect to one another such that each of the plurality of fluid samples can be permitted to pass through the blocking device, enter the mass spectrometer, and be analyzed by the mass spectrometer in turn.
- the mass spectrometer may comprise a quadrupole mass spectrometer or a time-of-flight mass spectrometer.
- the present invention can comprise any type of mass spectrometer or other desired analytical device. Additionally, it is understood that the present invention can comprise a multitude of separation methods, including, but not limited to high performance liquid chromatography, capillary electrophoresis, supercritical fluid chromatography, and capillary electrochromatography . As such, reference herein to "fluid sprays" include columns used to separate compounds into their component parts including HPLC, super critical fluid chromatography, capillary electrophoresis, affinity chromatography, capillary electrochromatography, and other separation methods.
- Fluid spray samples can also be delivered to the mass spectrometer interfacing either liquid or gaseous form, and they may be separated by infinity chromatography where compounds are partitioned between a solid support to which it is bound covalently or non-covalently and infinity receptor, ligand or other biological target, and a mobile phase.
- compounds are bound to a target receptor or other biological material can be separated from free ligand by interaction with a size exclusion material, such as size exclusion and gel permeation chromatography.
- the blocking device comprises a rotating disc which is positioned between the electrospray needle array and the mass spectrometer. The disc preferably has an off-center aperture dimensioned to receive only one electrosprayed sample therethrough.
- the electrospray needle array simultaneously targets each of the plurality of fluid sample electrosprays at different locations on the rotating disc, wherein these different locations and the center of the aperture are all generally equidistant from the center of the disc. Accordingly, rotation of the disc permits each fluid sample to pass therethrough in turn and enter the mass spectrometer .
- a microcomputer is also preferably included for determining the moments in time when each fluid sample enters the mass spectrometer. The determination of such moments in time is based upon determining the moments in time when each fluid sample passes through the aperture of the blocking device, knowing the orientation and speed of movement of the blocking device.
- a continuous mass spectral reading which is generated by the mass spectrometer can be sampled at particular moments in time corresponding to each fluid sample.
- the sampling of mass spectrograph readings for each fluid sample will preferably be performed again and again as the movement of the blocking device permits each fluid sample to pass therethrough such that a mass spectral reading can be made for each fluid sample over time, changing as different component compounds in the fluid sample elute out of the end of the various columns and pass into the mass spectrometer .
- the present invention provides a very efficient system for simultaneously analyzing a plurality of electrosprays, it is ideally suited for operation in conjunction with microtiter plate reaction well array systems.
- the compounds present in a plurality of reaction wells can be simultaneously sampled by the present system such that parallel electrospray analysis can be performed on these compounds.
- fraction collection can be performed such that purified compounds can be collected in a deep or shallow well microtiter plate format .
- an optical sensor can be used to determine a "home" position for the rotating plate at the start of each data acquisition, and an analog to digital converter can be used in conjunction with the motor rotating the disc in front of the sprayer assembly such that the signal of rising from each sprayer are recorded in real-time, permitting the signals to be separated and deconvoluted from one another.
- Fig. 1 is a schematic view of a first embodiment of the present invention comprising a rotating disc blocking device positioned between an electrospray needle array and a mass spectrometer .
- Fig. 1A is an enlarged view of the region encompassed by line 1A-1A in Fig.l, showing fraction collection in microtitre plate format .
- Fig. 2 is a schematic view corresponding to Fig. 1, but with the rotating disc rotated to a second position.
- Fig. 3 is a second embodiment of the present invention comprising a sliding plate blocking device positioned between an electrospray needle array and a mass spectrometer.
- Fig. 4 is a schematic view of a third embodiment of the present invention similar to Figs. 1 and 2, but with each column having a dedicated shuttering valve passing through a common non-rotating blocking device.
- Fig. 5 is an enlarged schematic view of the electrospray ionization region of the electrospray array of Figs. 1, 2, and 4.
- Fig. 6 is a schematic representation of the system corresponding to Figs. 1 to 5, shown operating in conjunction with an autosampler and HPLC pumps .
- Fig. 7 is a schematic representation of a system similar to Fig. 6, but instead showing 8 fluid separation columns.
- Fig. 8 is an example of an extracted ion chromatogram showing a graphical representation of mass spectrograph signals produced when operating the systems of Figs. 1, 2, 3 or 4.
- Fig. 9 is a perspective view of an eight column electrospray needle array, corresponding to the system of Fig. 7.
- Fig. 10 is a front elevation view of the eight column electrospray needle array of Fig. 10.
- Fig. 11 is a side elevation view of the eight column electrospray needle array of Fig. 10.
- Fig. 12 is a front elevation view of an optical sensor positioned in front of a rotating disc.
- Fig. 13 is a side elevation view corresponding to Fig. 12.
- Fig. 14 is a schematic view showing a control module for homing the rotating disc.
- Fig. 15 shows exemplary chromatograph, showing deconvolution of data corresponding to various fluid spray streams .
- Fig. 16 shows deconvolution of data of two different fluid streams .
- Fig. 17 shows an expanded chromatagram showing deconvolution of data representing two fluid streams.
- the present invention provides methods and apparati for analyzing the composition of a plurality of fluid samples and in particular for analyzing the mass spectrum of each of a plurality of fluid samples which are separated into component compounds by methods which may include liquid chromatography, capillary electrophoresis, supercritical fluid chromatography, and electrospray ionization-mass spectrometry and are then electrosprayed or flow injected by a direct transfer line into a mass spectrometer or any other desired sample analyzer.
- a plurality of separate fluid samples 11, 12, 13, and 14 are fluidly connected to respective columns 21, 22, 23 and 24.
- Fluid samples 11, 12, 13 and 14 may preferably comprise fluid samples drawn from the individual wells a of a conventional microtiter plate.
- Columns 21, 22, 23 and 24 each may comprise high performance HPLC columns, capillary electrophoresis columns supercritical fluid chromatography columns or flow injection transfer lines.
- the present application hereafter describes columns 21, 22, 23 and 24 comprising high performance HPLC columns, each containing a reactive resin that facilitates separation of a fluid sample passing therethrough into its component compounds. This is accomplished as each of the various component compounds within any fluid sample will react differently with the resin and thus take different amounts of time to pass through and be eluted out of the exit end of the column.
- Figs. 1 to 6 show four fluid separation columns 21, 22, 23 and 24. It is to be understood that any plurality of columns may be used in the present invention.
- Fig. 7 shows eight columns 21, 22, 23, 24, 25, 26, 27, 28, and Figs. 9 to 11 show an electrospray needle array adapted for use with eight columns .
- columns 21, 22, 23, 24, 25, 26, 27, and 28 may instead comprise flow injection transfer lines, capillary electrophoresis columns, supercritical fluid chromatography or any other system or device which can be used to direct a fluid sample into the entrance orifice of a mass spectrometer.
- each of columns 21, 22, 23 and 24 operate in parallel to separate fluid samples 11, 12, 13 and 14 into their respective component compounds which will elute out of the columns at different moments in time.
- the separated effluent passing out of columns 21, 22, 23 and 24 then passes into splitter tees
- 61, 62, 63 and 64 respectively, which are used to divert the majority of the HPLC effluent to dedicated fraction collectors, as will be described further herein.
- a small portion of the effluent passes out of the splitter tees, (typically less than 1%) and into the electrospray ionization region, (shown in detail in Fig. 5) , whereby it is converted into fine, narrowly focussed aerosol electrosprays 31, 32, 33 and 34 respectively.
- a much larger portion, of the portion of the effluent is diverted from the splitter tees, (typically more than 99%) , and is directed either to waste or to a dedicated fraction collector for compound isolation/purification, as will be explained.
- Electrospray needle array 20 preferably comprises either a single physical unit having a plurality of electrospray needles formed therein, or alternatively, array 20 may comprise a holding and targeting system for a plurality of separate conventional electrospray needles.
- Fluid samples 11, 12, 13 and 14 are separated into their respective component compounds at the same time by liquid chromatography columns 21, 22, 23 and 24. Accordingly, effluent electrosprays 31, 32, 33, and 34 containing the separated compounds from each of the plurality of columns 21, 22, 23 and 24 are directed into the electrospray ionization region through a multiple electrosprayer device.
- electrosprays 31, 32, 33 and 34 are directed in parallel with one another towards a rotating disc 40 which is positioned between the multiple electrospray needle array 20 and a mass spectrometer 50, as shown.
- Mass spectrometer 50 has an orifice plate 53 which preferably directs the ions formed in the aerosol electrosprays 31, 32, 33 and 34 into the mass spectrometer quadrupole region. Accordingly, electrosprays 31, 32, 33 and 34 are drawn toward opening 52, thus entering mass spectrometer 50.
- a skimmer 55 is provided to permit electrosprays 31, 32, 33 and 34 to enter the mass spectrometer, yet prevents other (neutral, un-ionized) particles from entering mass spectrometer 50. Should electrosprays 31, 32, 33 and 34 not be directed orthogonal to blocking device 40 as shown, ion optics can instead be used to focus electrosprays 31, 32, 33 and 34 into opening 52 of mass spectrometer 50.
- Disc 40 has an off-center aperture 42 passing therethrough, as shown.
- Aperture 42 is preferably dimensioned to be of a size so as to permit only one of the simultaneously electrosprayed fluids to pass therethrough, for reasons to be explained. Therefore, disc 40 operates as a blocking device to prevent the passage of all but one of the fluid samples from entering opening 52 of mass spectrometer 50.
- spray 31 passes through aperture 42 and enters mass spectrometer 50 at the same moment in time when electrosprays 32, 33 and 34 are blocked by disc 40. Accordingly, mass spectrometer 50 generates a mass spectrum analysis of spray 31 as spray 31 is received therein thereby providing a compositional analysis of its corresponding fluid sample 11.
- electrosprays 31, 32, 33 and 34 are each targeted by electrospray needle array 20 such that they contact disc 40 at locations 38 which are all generally equidistant from center 44 of disc 42, as shown. Moreover, the distance from the center of aperture 42 to disc center 44 is also generally equidistant to the distance from locations 38 to disc center 44. Accordingly, as disc 40 is rotated in direction R from the first position as shown in Fig. 1 to the second position as shown in Fig. 2, aperture 42 will then be moved to align with electrospray 32 such that electrospray 32 enters mass spectrometer 50 while electrosprays 31, 33 and 34 are blocked, thus providing a mass spectral analysis of its corresponding fluid sample 12.
- cyclical rotation of disc 40 will sequentially align aperture 42 with each of the locations 38 which correspond to each of electrosprays 31 to 34 such that electrosprays comprising fluid samples 11 to 14 will pass through aperture 42 in turn and enter mass spectrometer 50 one after another.
- a single complete rotation of disc 40 around its center 44 will result in a single mass spectrograph analysis being taken for each fluid sample.
- Disc 40 can either be rotated at a continuous speed or in a series of quick jumps between electrosprays when aligning aperture 42 with each of the various electrosprays 31 to 34. Rotation at a continuous speed produces longer gaps of time between each of the electrosprays entering the mass spectrometer since any particular electrospray only passes through aperture 42 when the aperture is aligned with that particular electrospray. For example, during the period of time in which disc 40 is rotated from the position shown in Fig. 1 to the position in Fig. 2, all electrosprays will be temporarily blocked from passing therethrough when aperture 42 is positioned between electrosprays 31 and 32.
- rotating disc 40 in a series of quick jumps so as to rapidly align aperture 42 with each of the various electrosprays 31, 32, 33 and 34 has the advantage that each electrospray can be analyzed for a longer period of time during each rotation of the disc, as the periods of time during which all electrosprays are blocked by the disc is reduced. Advantages also occur when synchronizing the stepping of a quadrupole rod voltage with the rotation of disc 40 as will be explained.
- Mass spectrometer 50 can comprise any type of mass spectrometry system, which may include, but are not limited to quadrupole and time-of-flight mass spectrometers, for reasons which will be explained.
- Mass spectrometer 50 operates to generate a mass spectrum corresponding to the molecular masses which it senses to be present in the fluid sample spray which is received therein. Accordingly, in the absence of the present invention, should two or more fluid samples be simultaneously electrosprayed into mass spectrometer 50, the mass spectrometer will not, by itself, be able to differentiate between these various electrosprays so as to determine which compounds are present in each of the electrosprays. Instead, the two or more electrosprays would simultaneously enter and therefore be simultaneously analyzed by the mass spectrometer such that although a particular molecular mass presence could be detected, it would not be possible to attribute this molecular mass to one or the other of the fluid sample electrosprays .
- mass spectrometer 50 is operated to continuously generate a mass spectrograph reading over a period of time during which each of the electrosprays 31, 32, 33 and 34 is sequentially received therein.
- each electrospray will be separately analyzed a number of times.
- mass spectrograph 50 By knowing the position of rotating disc 40 with respect to electrospray needle array 20 at various moments in time, it is then possible to determine when each electrospray 31, 32, 33 and 34 passed through aperture 42, into opening 52, and was analyzed by mass spectrograph 50.
- the continuous mass spectrum reading generated by mass spectrometer 50 can then easily be sampled at those moments in time which correspond to when each of the electrosprays is analyzed in mass spectrometer 50.
- a mass spectrum reading for each separate electrospray can be generated.
- a mass spectrum analysis over a continuous period of time during which disc 40 is rotated around a number of times, it is then possible to determine a mass spectrum reading for each fluid sample 11, 12, 13 and 14 corresponding to electrosprays 31, 32, 33 and 34 at a number of different moments in time, thus yielding a time-based chromatographic and mass spectral analysis of each of the various fluid samples.
- Such a time- based chromatographic and mass spectral analysis permits monitoring of each fluid sample to determine the moments in time when each of the component compounds in the separated fluid samples is eluted out of its respective column. For example, Fig.
- peaks 91 correspond to the molecular weights of effluent of fluid sample 11 over a period of time.
- peaks 92 correspond to the molecular weights of effluent of fluid sample 12 over a period of time, etc.
- each of samples 11, 12, 13, and 14 is sampled in a repetitive sequence. In the present invention, very rapid sampling can be achieved.
- blocking device 40 may be positioned as shown in Fig. 1 for 100 msec, rotated to the position shown in Fig. 2 in 10 msec, and then remain at the position shown in Fig. 2 for 100 msec. Accordingly, each of the separated fluid samples eluted from the columns can be repetitively analyzed.
- an electrospray needle array 20b is used in conjunction with a blocking plate 45 having an aperture 46 passing therethrough, as shown.
- Blocking plate 45 can be moved up or down in direction Dl as shown so as to selectively permit only one of the plurality of electrosprays 31 to 34, (in this illustration, spray 31), to enter the mass spectrometer 50.
- the operation of this second embodiment of the present invention is similar to that of the first embodiment, as described above, with the only substantial difference being that the blocking device comprises a blocking plate 45 which is moved back and forth in one direction, rather than being rotated around its center.
- This second embodiment is merely exemplary of an arrangement in which the sprayers and deblocking device are moved relative to one another.
- Other suitable arrangements wherein either the sprayer, the blocking device, or the sprayer and blocking device are moved relative to one another are also encompassed within the scope of the present invention.
- blocking plate 45 may instead be held at a fixed position and electrospray needle array 20b can be moved up or down in direction Dl so as to sequentially permit each of the electrosprays 31 to 34 to pass through aperture 46 and enter mass spectrometer 50. It is also to be understood that various combinations of movement of both electrospray needle array 20b and blocking plate 45 can also be used to selectively permit electrosprays 31 to 34 to enter mass spectrometer 50 one after another.
- a non-rotating blocking device 40b is equipped with a plurality of shutter valves 43 which can be individually selectively opened and closed so as to permit electrosprays 31 to 34 to enter mass spectrometer 50 one after another in turn.
- Valves 43 are preferably electronically controlled to selectively open and close one after another in turn, thereby permitting electrosprays 31 to 34 to enter mass spectrometer 50 in sequence. Accordingly, a blocking device comprising a rotating disc or translating plate is not required.
- a method of purifying each of the fluid samples is provided.
- purifying a fluid sample entails separating a fluid sample into its component compounds by liquid chromatography, and collecting that portion of the fluid sample which comprises a desired reaction compound in a sufficiently high concentration as the desired reaction compound is being eluted from a column. Accordingly, when purifying various fluid samples, expected molecular masses for each of these fluid samples will already be known and will be detected by the mass spectrometer, as follows.
- the voltage across quadrupole rods 54 is preferably set to a voltage level corresponding to the molecular mass of a desired reaction compound expected to be present in electrospray 31.
- the voltage across quadrupole rods 54 is preferably incrementally stepped to a voltage level corresponding to the molecular mass of a desired reaction compound expected to be present in electrospray 32.
- the rotation of disc 40 and the stepping of voltage across quadrupole rods 54 is synchronized such that the voltage level is stepped at or near the moment in time when disc 40 is rotated from the position shown in Fig. 1 to the position shown in Fig. 2.
- a small lead time effect may be present necessitating stepping the voltage very shortly after rotation of the disc from a first position to a second position to compensate for the time delay of the electrospray physically reaching mass spectrometer 50 after passing through aperture 42.
- electrospray 31 (corresponding to fluid sample 11), is first analyzed at a first voltage corresponding to a first desired molecular mass to determine the concentration of such a first desired molecular mass therein.
- Electrospray 32 (corresponding to fluid sample 12), is then analyzed at a second voltage corresponding to a second desired molecular mass to determine the concentration of such a second desired molecular mass therein. The process is repeated such that each of the fluid samples is analyzed in turn at a voltage level unique to its desired molecular mass.
- fraction collection (in which the portion of the separated fluid sample having a sufficiently high concentration of a desired reaction compound is diverted to a fluid collector), can be provided as follows.
- fraction collectors 37a, 37b, 37c and 37d are provided. It is to be understood that these fraction collectors may be physically separated from one another or alternatively, integrated into a single multi- chamber unit.
- Fig. 1A is an enlarged view of the region encompassed by line 1A-1A in Fig.l, showing fraction collection in microtitre plate format.
- the single multi -chamber unit can comprise a standard microtiter plate or plates such that purified or analyzed samples can be placed in a convenient liquid handling system format.
- fraction collector 37a is in fluid communication with fluid sample 11 by way of splitter tee 64.
- Tees 64 may each comprise Valco splitter tees which are configured to divert about 99% of the fluid eluted from the columns into the fraction collectors.
- valve 38a when mass spectrometer 50 determines that a desired compound is present in separated electrospray 31 in a sufficiently high concentration, (as indicated by a high signal intensity) , valve 38a is activated, sending the fluid into fraction collector 37a. At all other times, valve 38 is set to expel the fluid as waste W. As can be appreciated, fluid will pass out from tee splitters 61, 62, 63 and 64 into tubes 39 prior to electrosprays 31, 32, 33 and 34 actually reaching mass spectrometer 50.
- tubes 39 will preferably be fabricated of a length and diameter such that the partitioned fluid reaching valves 38 (typically more than 99% of the fluid eluted from the columns) , will be identical in composition to the fluid simultaneously being analyzed by mass spectrometer 50 (typically less than 1% of the fluid eluted from the columns) .
- the detection of a desired reaction compound in the fluid sample by the mass spectrometer will signal fraction collection to commence at the moment in time when such reaction compound reaches the fraction collection valve 38. Accordingly, any problems of time delay between detecting a desired reaction compound and collecting such reaction compound in a purified sample will be overcome by the present system.
- each of the electrosprays 31, 32, 33 and 34 will be analyzed over and over again in sequence. Accordingly, fluid diversion into each of fluid collectors 37a-37d is performed precisely in time when mass spectrometer 50 determines the presence of desired reaction compounds therein to be of sufficient concentration. It is also to be understood that more than one fluid collector can be used for each fluid sample spray such that different desired compounds (which are eluted at different times from the same column) , can be directed to different fluid collection chambers. This is preferably accomplished by having each of valves 38 set to direct fluid samples to a plurality of different fraction collectors. Accordingly, more than one desired reaction product can be purified for each fluid sample .
- a method of analyzing each of the fluid samples so as to determine their composition is provided.
- each of a plurality of fluid samples are electrosprayed in a manner so as to enter into a mass spectrometer 50 one after another.
- the present method of analyzing the mass spectrum of each fluid sample can be accomplished with the use of any type of mass spectrometer, including a quadrupole mass spectrometer, such as a PE-SCIEX API150 MCA Mass Spectrometer.
- the present invention is also particularly well suited for operation with a time of flight mass spectrometer, due to its ability to generate up to 10 full scan mass spectra per second.
- electrospray 31, (corresponding to fluid sample 11)
- electrospray 32 (corresponding to fluid sample 12)
- electrospray 32 is then analyzed with the voltage across the quadrupole rods being swept across a range to determine the composition of the fluid sample 12. The process is repeated such that each of the fluid samples is analyzed in turn.
- reaction compounds when the voltage level across quadrupole 54 corresponds to a molecular mass present in the electrospray, the presence of a reaction compound having this molecular mass will be detected as the quadrupole rods will allow ions in the electrospray having a molecular mass corresponding to the voltage to pass therethrough. As the quadrupole voltage is swept across the voltage range, a plurality of molecular masses (i.e.: reaction compounds), will be detected, and the composition of the particular electrospray will thereby be determined.
- the rotation of the disc is synchronized with the sweeping of the voltage across the quadrupole rods such that the disc is positioned (as in Fig. 1) to allow electrospray 31 to pass into mass spectrometer 50 while the voltage across quadrupole rods 54 is swept across a voltage range.
- disc 40 is rotated (as in Fig. 2) to allow electrospray 32 to enter mass spectrometer 50 with the voltage level again being swept across the voltage range.
- mass spectral analysis is sequentially performed on each fluid sample spray.
- a computer 60 is also preferably included in the present invention.
- Computer 60 monitors mass spectrometer 50 and disc 40 such that, by knowing the position of aperture 42 with respect to columns 21, 22, 23 and 24, the distances between electrosprayer needle array 20, disc 40 and mass spectrometer 50, and the speed of the flow electrosprays 31, 32, 33 and 34, computer 60 thereby determines the moments in time at which each of fluid samples 31 to 34 is analyzed by mass spectrometer 50.
- computer 60 can be used such that a continuous mass spectrum reading generated by mass spectrometer 50 can be deconvolutted using computer algorithms such that at particular moments in time the mass spectrum of each individual fluid sample can be determined.
- fluid samples 11, 12, 13 and 14 can comprise fluid samples as deposited in individual wells in a microtiter plate.
- a fluid sample autosampler 100 which may comprise a Gilson 215 Eight Channel Injector, can be used to simultaneously draw samples from eight wells in a microtiter plate and, together with HPLC pumps 102, can be used to load the samples onto fluid separation columns (21, 22, 23, 24, 25, 26, 27, and 28 in Fig. 7) . Accordingly, as is shown in Figs. 7, 9, 10, and 11, eight fluid samples can be analyzed in parallel.
- the present systems having four parallel electrospray heads, (Figs. 1 to 6 and 8), and the systems having eight parallel electrospray heads, (Figs. 7, and 9 to 11), are illustrative only in terms of the number of fluid samples. It is to understood that systems encompassing different numbers of parallel electrosprayers are also within the scope of the present invention.
- 12 sequential rows of 8 fluid samples can be analyzed or purified with the present invention. Specifically, after a first row of eight fluid samples have been simultaneously analyzed using the present system as set forth herein, a second row of reaction wells can be analyzed, etc.
- an ultraviolet detector 104 which may comprise a Shimadzu SPD10AV UV Detector, can be positioned between columns 21, 22, 23, 24, 25, 26, 27, and 28 and the electrospray needle array and blocking device (seen in detail in Figs. 1 to 5 , and shown schematically here as 106) .
- Figs. 12 and 13 show front and side view of an optical sensor to control movement of rotating disc.
- optical sensor 200 can be held in position above metal piece 202, which is attached to front surface of rotating disc 204. Accordingly, as metal piece 202 passes in front of optical sensor 200, the position of disc 204 can be repeatedy determined.
- a stepping motor 250 which may comprise an IMS hybrid stepping motor (M2-1713-S), can be powered by an IMS microstepping driver 252, which is connected to an IMS power supply 254 and a linx software communication module 256.
- a homing program software system 260 can be used to control the position of stepping of motor 250 with the output of sensor 200, such that the position of the rotating disc 204 can be known at all times.
- Fig. 15 shows data representative a multiple channel chromatagraph in which the signals 301, 302, 303, 304, 305, etc. can be distinguished from one another. Specifically, knowing the time at which each of signals 301, 302, 303, 304, and 305 were generated, it is possible to assign the respective signal to the fluid channel being sampled at that interval of time knowing the position of the rotating disc at various intervals of time.
- Fig. 16 shows data deconvolution for two fluid samples in which signals 400, which correspond to fluids emitted by a first fluid electrosprayer, are distinguished from signals
- signals 400 and 402 which are emitted by a correspond to fluids emitted by a second electrosprayer.
- signals 400 and 402 can be curvefitted to show representative curve 401 (representing signals 400) , and curve 403 (representing signals 402) , as shown .
- Fig. 17 shows a further example of a chromatagram of two signals in which signals 500, which correspond to fluids emitted by a first fluid electrosprayer are distinguished from signals 502, which are emitted by a correspond to fluids emitted by a second electrosprayer.
- signals 500 and 502 can be curvefitted to show representative curve 501 (representing signals 500) , and curve 503 (representing signals 502) , as shown.
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Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99930178A EP1086483A2 (en) | 1998-06-09 | 1999-06-08 | Parallel fluid electrospray mass spectrometer |
GB0103243A GB2356285B (en) | 1998-06-09 | 1999-06-08 | Parallel fluid electrospray mass spectrometer |
JP2000553978A JP2002518790A (en) | 1998-06-09 | 1999-06-08 | Simultaneous fluid electrospray mass spectrometer |
CA002343744A CA2343744A1 (en) | 1998-06-09 | 1999-06-08 | Parallel fluid electrospray mass spectrometer |
AU46770/99A AU766030B2 (en) | 1998-06-09 | 1999-06-08 | Parallel fluid electrospray mass spectrometer |
HK01107053A HK1036149A1 (en) | 1998-06-09 | 2001-10-08 | Parallel fluid electrospray mass spectrometer |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US8866598P | 1998-06-09 | 1998-06-09 | |
US60/088,665 | 1998-06-09 | ||
US09/185,450 US6066848A (en) | 1998-06-09 | 1998-11-03 | Parallel fluid electrospray mass spectrometer |
US09/185,450 | 1998-11-03 |
Publications (3)
Publication Number | Publication Date |
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WO1999065058A2 true WO1999065058A2 (en) | 1999-12-16 |
WO1999065058A3 WO1999065058A3 (en) | 2000-02-03 |
WO1999065058A9 WO1999065058A9 (en) | 2000-07-27 |
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ID=26778926
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/012905 WO1999065058A2 (en) | 1998-06-09 | 1999-06-08 | Parallel fluid electrospray mass spectrometer |
Country Status (9)
Country | Link |
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US (1) | US6066848A (en) |
EP (1) | EP1086483A2 (en) |
JP (1) | JP2002518790A (en) |
CN (1) | CN1321327A (en) |
AU (1) | AU766030B2 (en) |
CA (1) | CA2343744A1 (en) |
GB (1) | GB2356285B (en) |
HK (1) | HK1036149A1 (en) |
WO (1) | WO1999065058A2 (en) |
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US6833545B2 (en) | 2000-05-31 | 2004-12-21 | Amersham Biosciences Ab | Method and device for performing analyses in parallel |
US6501073B1 (en) | 2000-10-04 | 2002-12-31 | Thermo Finnigan Llc | Mass spectrometer with a plurality of ionization probes |
CN102709146A (en) * | 2012-06-15 | 2012-10-03 | 北京大学 | Multichannel rotary extractive electrospray ionization mass spectrometry ion source |
CN102709146B (en) * | 2012-06-15 | 2015-01-14 | 北京大学 | Multichannel rotary extractive electrospray ionization mass spectrometry ion source |
JP2015224905A (en) * | 2014-05-27 | 2015-12-14 | 国立大学法人 名古屋工業大学 | Mass analysis device |
US11710625B2 (en) | 2020-11-17 | 2023-07-25 | Karsa Oy | Unbiased ion identification by multiple ions |
Also Published As
Publication number | Publication date |
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US6066848A (en) | 2000-05-23 |
EP1086483A2 (en) | 2001-03-28 |
CN1321327A (en) | 2001-11-07 |
WO1999065058A3 (en) | 2000-02-03 |
GB2356285B (en) | 2002-06-19 |
JP2002518790A (en) | 2002-06-25 |
AU766030B2 (en) | 2003-10-09 |
GB0103243D0 (en) | 2001-03-28 |
CA2343744A1 (en) | 1999-12-16 |
HK1036149A1 (en) | 2001-12-21 |
AU4677099A (en) | 1999-12-30 |
WO1999065058A9 (en) | 2000-07-27 |
GB2356285A (en) | 2001-05-16 |
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